psychologywikiaorg-20200213-history
Genetic counseling: Colorectal Cancer Chemoprevention
Colorectal Cancer Chemoprevention Background *Colorectal Cancer **Second leading cause of cancer-related deaths in US ***Estimated 56,000 people die annually ***Surgical resection and chemotherapy or radiation are standard treatment procedures ***Lifetime risks for colorectal cancer ****General population 5% ****Family history of adenoma or CRC 15-20% ****HNPCC 80% ****FAP approaches 100% **Annual incidence 130,000 **When detected and treated while still localized 5 year survival exceeds 90% **Only 40% of cancers diagnosed while still localized **Current screening recommendations include: ***Annual fecal occult blood testing ***Flexible sigmoidoscopy every five years ***Colonoscopy every 10 years or double contrast barium enema every 5-10 years *Chemoprevention **Use of natural or pharmacologic agents to halt, reverse, or delay carcinogenesis **Mechanisms to protect against mutagens ***Inhibit uptake or activation ***Enhance DNA repair of apoptosis ***Modulate cellular activities ****Signal transduction ****Growth factor activity ****Hormonal activity ****Immune response ****DNA methylation **Development of chemotherapeutics ***Goal is to achieve an acceptable therapeutic index ****Therapeutic index is risk to benefit ratio *****Want benefits of chemoprevention to greatly outweigh risks *****Important for all therapeutic agents, but particularly those used for prevention ****Prevention of cancer may require years of therapy ***Four considerations in development ****Therapeutic regimen *****Dose *****Duration *****Route of administration ****Side effects ****Mechanistic specificity *****Agents ability to provide therapeutic development without affecting other pathways in body *****Reduces number of side effects ****Combinations with other chemotherapeutics *Chemoprevention in colon cancer **Alternative approach to screening to reduce mortality from colorectal cancer **Directed at preventing development of polyps that have potential to progress to colon cancer **Agents interfere with genetic alterations that lead to development of adenomas or their progression to cancer *Evaluation of chemotherapeutic effectiveness **Enhanced by increasing understanding of molecular events in carcinogenesis **Rely on different types of studies ***Epiemiological ***Animal studies ***Mechanisms of action of agents ***Controlled clinical trials **Measures of efficacy ***Difficult to determine what intermediate clinical events correlate with long term benefits ****Long term benefits *****Reduction in cancer incidence *****Reduction in cancer mortality *****Fewer or less invasive surveillance ****Clinical measurements *****Regression, suppression, and prevention of adenomas *****Examine adenoma number, size, burden, histopathology, cellular/molecular characteristics ***Trials usually are performed on only one risk cohort and may not apply to other cohorts or general population ****FAP ****HNPCC ****Inflammatory bowel disease ****Personal or family history of colorectal cancer ****General population Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) *Inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) **Catalytic enzymes that convert arachidonic acid into prostanoids ***Non-selective inhibitors inhibit both COX-1 and COX-2 ***Selective inhibitors inhibit only COX-2 ***Inhibiting COX enzymes causes increase in arachidonic acid ****Stimulates conversion of sphingomyelin to ceramide ****Ceramide induces apoptosis ***Apoptosis may also occur due to alterations in prostaglandin production and a decrease in angiogenic factors ***May also have COX-independent chemopreventive activities **Inhibit COX-1 by irreversible acetylation ***Constitutively expressed in most epithelial cell types ***Plays role in cytoprotection ***Inhibition of COX-1 in GI tract can cause ulceration and bleeding ***Not involved in colon carcinogenesis **Inhibit COX-2 by competitive inhibition ***Little basal expression in cells ****Induced by cytokines, mitogens, and growth factors ****Expression induced by cytokines, mitogens, and growth factors ***Overexpression may promote proliferation, inhibit apoptosis, and promote angiogenesis *Includes aspirin, sulindac, celecoxib, and rofecoxib *Aspirin **Case-control studies ***Show 40-50% reduction in risk of colonic adenomas or colorectal cancer ***Studies done on members of general population **Randomized controlled trial ***Only one has been completed ***Analyzed men in cohort examining the effects of aspirin on coronary artery disease ***Found no significant difference in risk of developing adenomas or cancer with use or aspirin ***Men were taking very low dose - may be a threshold dose that was not achieved in this study **Benefit seems to be greatest in people taking aspirin consistently for many years *Sulindac **Non-specific COX inhibitor **Observational and randomized trials ***Studied patients with FAP ***Showed substantial reduction in size and number of polyps ***Increase in number and size of polyps noted three months after sulindac Discontinued ***Development of new colorectal carcinoma reported in patient with FAP while taking sulindac **Randomized trial of primary chemoprevention ***Double-blind, placebo controlled ***Found sulindac did not slow development of adenomas in patients with FAP ***Found no significant difference in number of polyps between groups *Celecoxib **Selective COX-2 inhibitor **Randomized controlled trial ***Showed regression of polyps in patients with FAP by 28% ***Insufficient information about long-term effects **Only agent approved by FDA for treatment of adenomatous polyps *Risks of NSAIDs **Non-selective NSAIDs can cause ulceration and bleeding in GI tract **Concern about risk of cardiovascular effects of COX-2 inhibitors **Possible prothrombotic potential of COX-2 inhibitors **Important to assess long term effects because may require years of treatment *Future of NSAIDs **Current studies looking at celecoxib and related COX-2 inhibitor rofecoxib **Studies comparing effects of aspirin with selective COX-2 inhibitors **Development and testing of NO-releasing NSAIDs that may be safter and more effective than traditional NSAIDs Other Chemopreventive Agents *DFMO (a-difluoromethylornithine) **Irreversible inhibitor of enzyme ornithine decarboxylase (ODC) ***ODC is enzyme involved in biosynthesis of polyamines ***Polyamines are promoters of cell proliferation ***ODC activity and polyamine levels significantly elevated in colorectal adenomas and cancers compared to normal tissues **Phase II clinical trials in 1980's ***Pulled due to limited efficacy ***Severe side effects noted ****Thrombocytopenia ****Nausea and vomitting ****Abdominal pain ****Diarrhea ****Reversible hearing loss **Recent early trials show DFMO may be effective at low doses ***Dose-limiting ototoxicity only side effect ***Now being tested in Phase II/III trials in those at risk for colorectal, bladder, or skin cancer ***May have additive effect when used with COX inhibitors *Folate **Individuals with high dietary folate intake have lower incidence of colorectal cancer ***Greatest benefit if using supplements ***May require years of use for benefit to be seen **Mechanism of action unknown *Calcium **Some studies show supplements decrease proliferation of colorectal epithelium ***Within one year of use ***Dose required to see effect still unknown **May inhibit carcinogenesis by binding bile acids and fatty acids in bowel lumen *Hormone Replacement Therapy (HRT) **May provide 20% reduction in risk for colorectal cancer **Estrogens may decrease production of secondary bile acids by decreasing insulin-like growth factor I *Vitamins, antioxidents, fiber **Data from prospective studies show no effect in rate of adenoma formation with vitamin or antioxidant supplements **Studies show very weak protective effect of increased dietary fiber Notes The information in this outline was last updated in 2002. Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling